Digoxin complexes

ABSTRACT

Digoxin forms novel complexes with dihydroxybenzenes such as hydroquinone, resorcinol and pyrocatechol. These complexes exhibit rapid dissolution and high solubility in aqueous media. These complexes are useful in the treatment of cardiac insufficiency.

United States Patent H91 Higuchi Oct. 1, 1974 DIGOXIN COMPLEXES 3,514,441 5/1970 Satoh et al 260/2105 Inventor: Taker" g c e ce ns 3,531,462 9/1970 Satoh et al 260/2105 [73] Assignee: IltlTERx Research Corporation, Primary Examiner johnnie R. Brown Lawrence Assistant ExaminerCary B, Owens [22] Filed: June 29, 1973 Attorney, Agent, or FirmCharles N. Blitzer [21] Appl. No.: 375,052

[57] ABSTRACT g 260/ Digoxin forms novel complexes with dihydroxybem zenes such as hydroquinone, resorcinol and pyrocate [58] Field of Search 260/2105 ch01. These complexes exhibit rapid dissolution and [56] References Cited high solubility in aqueous media. These complexes are useful in the treatment of cardiac insufficiency. UNITED STATES PATENTS 3,223,587 12/1965 Wilkinson 260/2105 5 Claims, No Drawings DIGOXIN COMPLEXES BACKGROUND OF THE INVENTION pounds very similar in structure, and it is difficult to isolate in its pure form. However, the United States Pharmacopeia requires that the compound used as a drug be at least 96 percent pure as measured by the specific assay in the compendia. When digoxin is administered orally as a solid dosage form, the maximum (peak) digoxin plasma level of patients receiving ordinary therapeutic doses is 0.1 to 2.1 nanograms per millimeter (Lindenbaum, J et al., The New England Journal Medicine, Dec. 9, 1971, page 1344; Huffman, D. H., et al., JAMA, Vol. 222, No. 8, page 957, Nov. 20, 1973; Wagner, .1. G., et al., JAMA, Vol. 224, No. 2, page 199, Apr. 19, 1973). Within this range, toxic effects may be observed at the high values and no effect at the low values. However, when the drug plasma level is about 3.3 nanograms per millimeter, patients experience toxic effects. Due to the small difference between the maximum therapeutic and minimum toxic plasma levels, a reliable and reproducible dosage form is essential. It has been shown that blood levels obtained by using the tablet made either by different manufacturers or different lots made by the same manufacturer differ significantly in achieving reproducible blood levels of Digoxin (Lindenbaum, J., et al., The New England Journal of Medicine, Dec. 9, 1971, page 1344; Wagner, .1. G., et al., JAMA, Vol. 224, No. 2, page 199, Apr. 19, 1973; Be'rtler, A., et al., The Lancet, page 708, Sept. 30, 1972). Digoxin has extremely low water solubility, about 80 to 100 micrograms per milliliter. In addition, the rate of dissolution is extremely slow and is considerably dosage form dependent. Thus, the dissolution rate is the limiting and determining factor in the rate and extent of absorption of digoxin in the body. Because digoxin is so slowly dissolved and absorbed, it is difficult for physicians to accurately adjust the dosage to achieve the desired digoxin concentration in the blood. Therefore, it is highly desirable to have available for medical use a form of digoxin which would dissolve much more rapidly and provide reproducibility in the gastrointestinal fluids when administered orally in a tablet dosage form so that blood levels of the drug could be accurately related to the dosage and result in reproducible blood levels.

A number of digoxin derivatives have been prepared in an attempt to alter the physical or pharmacological properties of the drug. Alterations of the digitoxose portion of the molecule include the formation of ethers (US. Pat. No. 3,538,078, German Pat. No. 1,961,034) and formation of acylates (Belg. Pat. No. 750,875, German Pat. No. 2,019,967, US. Pat. No. 3,514,441). Alterations of the steroid and lactone portion of the digoxin molecule include digoxin l5',l6'-diacetates (Belgian Pat. No. 749,680) and substitution at the 22 carbon (Belgian Pat. No. 751,768, German Pat. No. 2,052,634). However, the need for a rapidly soluble form of digoxin which does not alter the pharmacological activity of the drug remains.

SUMMARY OF THE INVENTION The first aspect of this invention relates to the novel complexes formed by digoxin and dihydroxybenzenes such as pyrocatechol, resorcinol and hydroquinone. These complexes are represented by the formula shown below wherein D represents digoxin, A represents a dihydroxybenzene selected from pyrocatechol, hydroquinone or resorcinol and n is 1, 1%, or 2.

D'An

In another aspect, this invention relates to administration of digoxin to warm-blooded animals in the form of the novel complexes of this invention, pharmaceutical compositions of the novel complexes and to pharmaceutical compositions of the complexes containing an antinucleating agent or an excess of the dihydroxybenzene. The dihydroxybenzene in these compositions may be present from H to 20 percent by weight of the composition, or more preferably, from A to 2 percent by weight of the composition.

Finally, this invention also relates to a novel means forpurifying digoxin. The novel complexes of this invention, when formed from a solution of impure digoxin, precipitate and may be separated from themother liquor in which the impurities remain. Separation of the crystalline complex and subsequent removal of the dihydroxybenzene effectively isolates digoxin from closely related impurities which are otherwise difficult to separate.

DESCRIPTION OF THE PREFERRED EMBODIMENTS are the pyrocatechol complexes having the ratio of digoxin to pyrocatechol of 1:1, 11% and 1:2, the resorcinol complexes having the ratio of digoxin to resorcinol of 1:1, lzl-l and 1:2 and the hydroquinone complexes having the ratios of digoxin to hydroquinone of 1:1, l:1 /2 and 1:2. Of these, the hydroquinone complexes are preferred for rapid solubility, ease of preparation, and safety.

The complexes of this invention are extremely rapidly soluble in water in comparison with pure crystalline digoxin. However, these complexes do not remain intact in solution but immediately dissociate upon dissolution. Thus, digoxin is available for absorption rapidly. Dosage levels for the complex are comparable to the well-known dosage levels for digoxin. The complex could be administered, for example, as a tablet containing the equivalent of 500 or 250 micrograms of digoxin. The dihydroxybenzenes do not interfere with the digoxin activity, and in these quantities are not significantly toxic. For example, hydroquinone has been ingested by man at 500 mgm per day for five months with no ill effects. (Proc. Soc. Exp. Biol. Med, 84, 684(1953).

The complexes of this invention are formed by contacting a solution of dihydroxybenzene with the digoxin and agitating the mixture for an extended period. In practice, the complexes of this invention are formed by contacting the digoxin in solution with excess complexing reagent. Since the digoxin, the dihydroxybenzene and the complex are in equilibrium, the excess of the complexing agent will favor the formation of the complex and will also tend to depress the solubility of the complex in the mother liquor. The actual ratio of complexing reagent to digoxin is dependent upon solvent, temperature and nature of complexing agent. In general, the complexing reagent should be present in the range of 0.05 to 0.95 of its maximum solubility in the solvent used. Oxygen can be excluded from the reaction mixture since oxygen can interact with the complexing reagents. The complexes of this invention can also be formed in the presence of an antioxidant (oxygen scavenger). The use of antioxidants is preferred in an aqueous system but is not essential. For example, sodium busulfite is an antioxidant compound which can be used. The molar concentration of the antioxidant can range from O to equal to the concentration of the dihydroxybenzene in solution. However, addition of 4 to molar percent of the antioxidant based on the concentration of dihydroxybenzene is adequate. The complexing reagent solution and the digoxin should be contacted for long periods of time under conditions of a good agitation. Stirring periods of 72 hours or longer give good results, but the exact period is not critical. The reaction proceeds at ambient pressure. The individual complexes within the scope of this invention are precipitated from the reaction mixture by seeding the reaction mixture with seed crystals of the desired product. Following the agitation period, the precipitated digoxin complex is filtered from the mother liquor and as much as the filtrate as possible is removed from the filter cake. Note that it is not possible to purify the complex by recrystallization since the complex dissociates in solution. The filtered complex can be dried. Drying this complex under vacuum might be used to remove excess complexing reagents which remained in the filter cake.

It has been found that the formation of the complex is selective in that the impurities usually associated with digoxin, digoxigenin and digoxigenin substituted by one or two digitoxose units, are present in concentrations below that required for impurity-hydroxybenzene complexes to be precipitated. Thus, the complex may be formed to separate digoxin from the closely related impurities. It is desirable to select as the solvent for complex formation a solvent which has high solvency for impurities present and for complexes formed by such impurities and has low solvency for digoxin complex such that impurities tend to remain in solution and digoxin complex would precipitate. The complex precipitated and filtered from the mother liquor will contain few of the impurities, and when the complex is shaken with a solvent, it immediately dissociates leaving purified digoxin and the complexing reagent. The solvent is usually one in which the complexing reagent is relatively soluble and digoxin is relatively insoluble. The complexing reagent in solution may then be conveniently removed and pure digoxin isolated by methods well known to those skilled in the art, such as filtration of the precipitated digoxin, extraction, etc. The preferred solvents are diethyl ether or water, but other solvents might be used without departing from this invention.

The digoxin complexes of this invention may be formulated and processed to prepare pharmaceutical compositions for oral administration by methods well known to those skilled in this art. The digoxin complexes can be formulated in a manner similar to formulations presently used for digoxin. Since the complex dissociates in the presence of most solvents, wet granulation processes should be avoided during the compounding of the dosage form. The direct compression technique, well known to those in the art, can be used where the complex is dry blended with portions of the pharmaceutical excipients, screened or milled, and then blended with the remainder of the excipients.

An additional facet of the formulation of digoxin complexes should be noted. In tablet form, the very rapid solubility of the digoxin complexes, which is the object of this invention, requires special considerations. When a tablet is administered, the tablet first absorbs water or gastric juice and then disintegrates or dissolves. Since the digoxin complex rapidly dissociates and the digoxin goes rapidly into solution in the water that was absorbedby the tablet, the concentration of digoxin could exceed its maximum solubility of the tablet does not disintegrate rapidly, thus precipitating digoxin. In order to avoid this, it is important that the tablets are formulated so they disintegrate before significant amounts of the digoxin complex dissolves and digoxin precipitates. This premature precipitation of pure digoxin can be avoided in several ways. First, the formulation must contain effective disintegrants in optimum proportions. Second, the tablet can contain an excess from U to 20 percent of the tablet weight of the dihydroxybenzene complexing reagent. The presence of excess dihydroxybenzene will initially depress the solubility of the digoxin complex, permitting the tablet to disintegrate before digoxin can be precipitated within the tablet. A more preferred range for excess quantities of the complexing reagent is from A to 2 percent.

Another means of initially depressing the precipitation of digoxin within the tablet prior to disintegration is to include antinucleating agents in the formulation. Antinucleating agents are well known to those skilled in the art of formulation of pharmaceuticals. Examples of such antinucleating agents are polyvinyl alcohol, lecithin, dextran and various cellulose derivatives such as carboxymethylcellulose and methyl cellulose. Care must be taken to be sure the antinucleating agent chosen is not reactive with either digoxin or the digoxin complex. The preferred antinucleating agent is polyvinyl alcohol and the preferred concentration for the antinucleating agent is 0.1 to 10 percent by weight.

This invention will be further illustrated by the following examples.

Example 1 Preparation of the Complex Digoxin, 46.86 grams (6 X 10' moles), sodium bisulfite, 1.04 grams (1 X 10 moles), and hydroquinone, 66.3 grams (6 X 10 moles), were placed in an amber glass vessel and one liter of water was added. The mixture was then thoroughly flushed with a stream of nitrogen and the vessel was sealed with a polyethylene-lined cap. The mixture was rotated in a constant temperature bath at 25C. for 72 hours. At the end of 72 hours, the mixture was filtered and the filter cake pressed and dried at ambient temperature under vacuum. The yield of the 1:1 complex was about 60 grams.

Example 2 Digoxin, 46.86 (6 X 10 moles), sodium bisulfite, 1.04 grams (1 X 10 moles), and resorcinol, 55.1 grams (5 X 10 moles), were placed in an amber glass vessel and one liter of water was added. The mixture Ingredients of the complexes of this invention can be formulated in i Y a similar manner.

Example 6 The pharmaceutical manufacture of three tablet formulations designed to prevent precipitation of digoxin particles from a solution of the complex is shown below:

Formulation 3 Wt./Tablet Formulation 2 Wt./Tablet Formulation l Wt./Tablet 0.641 mgm 0.64] mgm 0.641 mgm droquinone Complex Polyvinyl Alcohol Hydroquinone, USP Microcry- 0.700 mgm 0.700 mgm 2.800 mgm 2.800 mgm 6.000 mgm 6.000 mgm 6.000 mgm stalline Cellulose Magnesium 0.150 mgm 0.150 mgm 0.150 mgm Stearate, USP

Lactose,

pr Drie d, USP TOTAL 24.709 mgm 24.709 mgm 24,709 mgm 35.000 mgm 32.200 mgm 34.300 mgm Example 3 Digoxin, 46.86 g (6 X moles), sodium bisulfite, 1.04 grams (1 X 10 moles), and pyrocatechol, 77.1 grams (7 X 10' moles), were placed in an amber glass vessel and one liter of water was added. The mixture was then thoroughly flushed with a stream of nitrogen and the vessel was sealed with a polyethylene-lined cap. The mixture was rotated in a constant temperature bath at C for 96 hours. At'the end of 96 hours, the mixture was filtered and the filter cake pressed and dried at ambient temperature under vacuum. The yield of the complex was about 60 grams.

Example 4 Rate of Dissolution of the Complex 5 Mgm of 100/200 mesh powders of digoxin and a digoxin-hydroxyquinone complex were added to separate vessels containing 500 milliliters of water. Each mixture was maintained at 25C. and stirred at a speed of 50 revolutions per minute. Samples were periodically withdrawn and assayed for digoxin in solution. After one minute, the amount of digoxin dissolved was 2.19 mgm for the complex and 0.047 mgm for the digoxin powder...

Example 5 The pharmaceutical manufacture of a tablet formulation is shown below:

Ingredients Wt./Tablet All of the complexes of this invention can be formulated in a similar manner.

Example 7 The purification of digoxin through preparation of the complex is shown below:

i ether, and dried in vacuum. The resulting digoxin was Digoxin-Hydroquinone complex Microcrystalline Cellulose Magnesium Steurate, USP Lactose. Spray Dried, USP

TOTAL 0.64l mgm 6.000 mgm 0.150 mgm 28.209 in m 35.000 mgm the equivalent of 0.4, 0.3, 0.2, 0.1 mgm digoxin as cornplex, and the like, are prepared in a similar manner. All

.v tqal y. cent Acomplex of the formula:

wherein H D is digoxin, A is a dihydroxybenzene selected from the group consisting of resorcinol, hydroquinone and pyrocatechol, and n is 1, 1 /2 or 2. 2. The complex of claim 1 wherein A is hydroquinone.

3. The complex of claim 1 wherein A is resorcinol. 4. A method for purifying impure digoxin consisting essentially of:

l. introducing impure digoxin into a suitable solvent solution of a complexing agent selected from the group consisting of resorcinol and hydroquinone to form a solid digoxin complex, whereby said com- 7 8 plex is precipitated while the impurities found in complexing agent, and said digoxin remain in solution, 4. removing said purified digoxin from said solution. 2. separating said precipitated solid digoxin complex from said solution, 5. The method of claim 4, wherein said solvent is a 3. introducing said separated solid digoxin complex member selected from the group consisting of water into a suitable solvent, whereby said-complex imand diethyl ether.

mediately dissociates into purified digoxin and said 

1. A COMPLEX OF THE FORMULA:
 2. The complex of claim 1 wherein A is hydroquinone.
 2. separating said precipitated solid digoxin comPlex from said solution,
 3. introducing said separated solid digoxin complex into a suitable solvent, whereby said complex immediately dissociates into purified digoxin and said complexing agent, and
 3. The complex of claim 1 wherein A is resorcinol.
 4. A method for purifying impure digoxin consisting essentially of:
 4. removing said purified digoxin from said solution.
 5. The method of claim 4, wherein said solvent is a member selected from the group consisting of water and diethyl ether. 